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Novel Enhanced Sampling Methods in Multiscale Modeling

多尺度建模中的新型增强采样方法

基本信息

批准号：
EP/R013012/2
负责人：
Edina Rosta
金额：
$ 69.02万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR013012%2F2
关键词：
Novel Enhanced Sampling Methods Multiscale

项目摘要

Computer-based technologies are becoming one of the most promising novel approaches due to continuously accelerated growth of both hardware processing power and software algorithm efficiency. One recent example includes machine learning algorithms that revolutionised data analysis in computer science, and lead to new computer games, visual recognition, and other applications that overtake human performance in many cases. Here, we propose to perform atomistic molecular simulations using novel enhanced sampling algorithms. Most biologically important processes take place on significantly longer timescales than those accessible to current computer simulations. Therefore, to obtain meaningful and accurate results regarding the kinetics and conformational dynamics of complex molecular systems, we use algorithms that enhance the sampling using parallel calculations with different biases. Developing more optimal biasing algorithms will allow us to model faster and more accurately the key biological processes of interest, including ligand binding, protein conformations, etc.Here we aim to use statistical algorithms inspired by machine learning to develop novel enhanced sampling methods for molecular simulations. Novel algorithms can be applied to a wide range of molecular modeling problems. We will focus on phosphate catalytic enzymes, and study key DNA processing enzymes to reveal the catalytic mechanism in these systems.Due to the essential nature of phosphate catalytic enzymes in most biological processes, a large number of drugs in current clinical practice also target phosphate-processing enzymes treating a wide range of diseases. Examples include reverse transcriptase and integrase inhibitors used against HIV and hepatitis B, proton pump inhibitors used in gastric diseases, kinase, PARP and topoisomerase inhibitors used against a large number of cancers. Studying phosphate catalytic systems with modern molecular modeling methods will enable fundamental advances in our current knowledge of the molecular basis of life. It will also create opportunities for rational development of better drugs to fight diseases.

由于硬件处理能力和软件算法效率的不断加速增长，基于计算机的技术正在成为最有前途的新方法之一。最近的一个例子是机器学习算法，它彻底改变了计算机科学中的数据分析，并导致了新的计算机游戏，视觉识别和其他在许多情况下超越人类表现的应用。在这里，我们建议使用新的增强采样算法进行原子分子模拟。大多数生物学上重要的过程发生在比目前计算机模拟更长的时间尺度上。因此，为了获得关于复杂分子系统的动力学和构象动力学的有意义和准确的结果，我们使用使用具有不同偏差的并行计算来增强采样的算法。开发更优化的偏置算法将使我们能够更快，更准确地建模感兴趣的关键生物过程，包括配体结合，蛋白质构象等。在这里，我们的目标是使用受机器学习启发的统计算法来开发用于分子模拟的新型增强采样方法。新的算法可以应用于广泛的分子建模问题。我们将以磷酸催化酶为研究重点，通过对关键的DNA加工酶的研究，揭示这些系统中的催化机制。由于磷酸催化酶在大多数生物过程中的本质，目前临床上大量的药物也以磷酸加工酶为靶点，治疗各种疾病。实例包括用于对抗HIV和B型肝炎的逆转录酶和整合酶抑制剂、用于胃病的质子泵抑制剂、用于对抗大量癌症的激酶、PARP和拓扑异构酶抑制剂。用现代分子模拟方法研究磷酸盐催化体系将使我们目前对生命分子基础的认识取得根本性进展。它还将为合理开发更好的药物来对抗疾病创造机会。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Resolving sub-angstrom ambient motion through reconstruction from vibrational spectra.

DOI：
10.1038/s41467-021-26898-1
发表时间：
2021-11-19
期刊：
Nature communications
影响因子：
16.6
作者：
Griffiths J;Földes T;de Nijs B;Chikkaraddy R;Wright D;Deacon WM;Berta D;Readman C;Grys DB;Rosta E;Baumberg JJ
通讯作者：
Baumberg JJ

Molecular Vibration Explorer: an Online Database and Toolbox for Surface-Enhanced Frequency Conversion and Infrared and Raman Spectroscopy.

DOI：
10.1021/acs.jpca.2c03700
发表时间：
2022-07-21
期刊：
The journal of physical chemistry. A
影响因子：
0
作者：
Koczor-Benda Z;Roelli P;Galland C;Rosta E
通讯作者：
Rosta E

Molecular Screening for Terahertz Detection with Machine-Learning-Based Methods

DOI：
10.1103/physrevx.11.041035
发表时间：
2021-11-18
期刊：
PHYSICAL REVIEW X
影响因子：
12.5
作者：
Koczor-Benda, Zsuzsanna;Boehmke, Alexandra L.;Rosta, Edina
通讯作者：
Rosta, Edina

Combined Free-Energy Calculation and Machine Learning Methods for Understanding Ligand Unbinding Kinetics.

DOI：
10.1021/acs.jctc.1c00924
发表时间：
2022-04-12
期刊：
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
影响因子：
5.5
作者：
Badaoui, Magd;Buigues, Pedro J.;Berta, Denes;Mandana, Gaurav M.;Gu, Hankang;Foldes, Tamas;Dickson, Callum J.;Hornak, Viktor;Kato, Mitsunori;Molteni, Carla;Parsons, Simon;Rosta, Edina
通讯作者：
Rosta, Edina

Full Control of Plasmonic Nanocavities Using Gold Decahedra-on-Mirror Constructs with Monodisperse Facets.

使用具有单分散面的镜上金十面体结构完全控制等离子体纳米腔。

DOI：
10.1002/advs.202207178
发表时间：
2023-04
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
0
作者：
Hu S;Elliott E;Sánchez-Iglesias A;Huang J;Guo C;Hou Y;Kamp M;Goerlitzer ESA;Bedingfield K;de Nijs B;Peng J;Demetriadou A;Liz-Marzán LM;Baumberg JJ
通讯作者：
Baumberg JJ